N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Abstract

Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo [b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H 1 receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT 1A , 5-HT 1E , 5-HT 2A , 5-HT 2B , 5-HT 7 receptors, the a 1B -adrenergic receptor, and the M 1 , M 3 , and M 5 muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT 1D , 5-HT 2C , 5-HT 3 , 5-HT 5 , 5-HT 6 , a 1A , a 2A , a 2B , a 2C , H 2 , M 2 , M 4 , and dopamine D 1 , D 2 , D 3 , and D 4 receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K i of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT 1A receptor. N-Desalkylquetiapine was an antagonist at 5-HT 2A , 5-HT 2B , 5-HT 2C , a 1A , a 1D , a 2A , a 2C , H 1 , M 1 , M 3 , and M 5 receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT 1A agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.

Quetiapine Fumarate Extended‐Release for the Treatment of Major Depression With Comorbid Fibromyalgia Syndrome: A Double‐Blind, Randomized, Placebo‐Controlled Study

“…Despite extensive research, the etiology of pain in fibromyalgia remains elusive, although central sensitization has emerged as a leading theory explaining the mechanism of disease (10). The analgesic effects of quetiapine XR may be mediated in part by its dopaminergic actions as well as its effects on both the serotonergic and noradrenergic systems (24,25,30). Our study is the first to show that quetiapine XR significantly improves measures of depression and pain in patients with a dual diagnosis of MDD and fibromyalgia and may therefore constitute a rational choice to target both conditions concurrently.…”

“…In vitro studies have shown that the parent compound, quetiapine fumarate, is a partial agonist at serotonin receptor 1A (5-HT 1A ) and an antagonist at 5-HT 2A and 5-HT 3A , D 1 and D 2 dopamine receptors, H 1 histamine receptor, and ␣ 1 -and ␣ 2 -adrenergic receptors (24). Furthermore, one of its major metabolites, norquetiapine, has been shown to have a moderate affinity for the norepinephrine reuptake transporter and a 10-fold more potent effect than quetiapine at 5-HT 1A (25). This receptor-binding profile likely explains the demonstrated antidepressant efficacy of quetiapine XR as monotherapy for the treatment of both bipolar (26) and unipolar depression (27)(28)(29).…”

Dispensed prescriptions for quetiapine and other second-generation antipsychotics in Canada from 2005 to 2012: a descriptive study

“…4,9,[39][40][41][42] Norquetiapine, the major metabolite of quetiapine, is anticholinergic and can produce blurred vision and dry mouth among other anticholinergic side effects. 9,14 Relevant to its use to treat anxiety and insomnia, quetiapine has been repeatedly associated with withdrawal reactions as well as abuse and dependence. 43,44 In addition to concerns over the use of quetiapine in treating patients with major depression, anxiety or sleep problems, we have concerns about inadequate monitoring of patients of all ages who are taking quetiapine and other antipsychotics.…”

Tedavide Hızlı Salınımlı ve Uzatılmış Salınımlı Formülasyonların Farkları

“…Ketiapinin major depresyon üzerindeki etkisinin, aktif metaboliti olan norketiapinin rolü olduğu ve bu etkiyi noradrenalin taşıyıcısı (NET) üzerindeki antagonist etkisiyle ilişkili olduğu düşünülmektedir (35)(36)(37). Ketiapin XR kararlı durumdayken PET ile NET'in değerlendirildiği sağlıklı gönüllülerde, NET'in aktivitesinde azalma saptanmıştır (38).…”